Effect of imidazo[1,2-α]pyrimidine derivatives on leukocyte function

Abstract:

Objective and Design: A series of six imidazo[1,2-α]pyrimidine (IP) derivatives were evaluated for their effects on leukocyte functions in vitro as well as on the inflammatory response induced by zymosan in the mouse air pouch.¶Materials and Subjects: Human neutrophils and murine peritoneal macrophages were used for in vitro assays. Mouse air pouch was performed in Swiss mice.¶Treatment: Test compounds were incubated with either human neutrophils or mouse peritoneal macrophages at concentrations not showing cytotoxic effects. For in vivo experiments, IPs were injected into the air pouch.¶Methods: Elastase and myeloperoxidase release, superoxide generation and LTB₄ production were assayed in human neutrophils treated with different stimuli. Mouse peritoneal macrophages were stimulated with lipopolysaccharide (LPS), followed by determination of nitrite and PGE₂ levels in supernatants. Zymosan was injected into six days-old mouse air pouches. Dunnett's t-test was employed for statistical analysis.¶Results: All IPs inhibited human neutrophil degranulation with IC₅₀ values in the μM range. IP-1, IP-2 and IP-5 also decreased superoxide generation. In LPS-stimulated macrophages, IP-4 and IP-6 inhibited nitrite production with a moderate reduction in PGE₂ generation. In addition, these two compounds at 100 nmol/pouch inhibited leukocyte migration and LTB₄ levels in the exudate of the mouse air pouch.¶Conclusions: Imidazo[1,2-α]pyrimidines are a class of compounds with antiinflammatory potential.